Biomarkers during COVID-19: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Beatrix Zheng and Version 1 by Chao-Min Cheng.

As the COVID-19 (Coronavirus disease 19) pandemic spreads worldwide, the massive numbers of COVID-19 patients have created a considerable healthcare burden for every country. The clinical spectrum of SARS-CoV-2 infection is broad, ranging from asymptomatic to mild, moderate, severe, and critical. Most COVID-19 patients present with no or mild symptoms, but nearly one-fifth of all patients develop severe or life-threatening complications. In addition to localized respiratory manifestations, severe COVID-19 cases also show extra-pulmonary complications or induce multiorgan failure. Identifying, triaging, and treating patients at risk early is essential and urgent. 

  • COVID-19
  • SARS-CoV-2
  • biomarker
  • cytokine storm
  • point-of-care testing

1. Immunological and Inflammatory Response to SARS-CoV-2 Infection

As the SARS-CoV-2 virus enters host cells, binding to the angiotensin-converting enzyme 2 (ACE-2) receptor, viral replication in the cytoplasm releases many virions, causing local infection of neighboring cells and a viremia-induced systemic immune response [5][1]. Both innate and adaptive immune responses are therefore activated. Meanwhile, the SARS-CoV-2 also induces the secretion of soluble serum and urine ACE2, further releasing a vast quantity of cytokines and causing a systemic inflammatory response [14][2]. Excessive cytokines stimulate and recruit immune cells, causing dysregulated, overcompensating host responses leading toward “cytokine storm syndrome” [3,9][3][4]. This dysregulated immune response is a life-threatening, urgent-care condition that may be progressively characterized by persistent fever, nonspecific muscle pain, hemodynamic instability, disseminated intravascular coagulation (DIC), multiorgan failure, and, in the absence of suitable treatment, death [13][5].

1.1. Cytokines

The rapid deterioration of severely affected COVID patients may be attributable to an over-reacting immune system. This response may evolve from multiple pathways, including, but not limited to, NF-κB signaling, the JAK/STAT pathway, the NLRP3 pathway, and granulocyte macrophage-colony stimulating factor (GM-CSF) activation pathways [13,15][5][6]. While SARS-CoV-2 virus infects epithelial cells, the above immune pathways are activated, and several pro-inflammatory cytokines are released, including interleukin 1β, (IL-1β), IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, TNF-α, and interferons (INFs) [3,9,13][3][4][5]. Elevated cytokine levels result in the recruitment of immune cells such as macrophages, T cells, and neutrophils to the infected area. Meanwhile, released serum cytokines such as interleukin-6 (IL-6), lead to increased synthesis of prototypic acute phase reactants, such as C-reactive protein (CRP), from the liver and into the bloodstream. Eventually, all of these dysregulated immune responses elicit various sequelae, such as the destabilization of endothelial cell-to-cell interactions, the destruction of the capillary and vascular barrier, tissue damage, and multiple organ failure, which may eventually result in the death of the infected individual [3,16][3][7].
The relationship between interleukin-6 and COVID-19 severity has been investigated by many studies [17,18,19][8][9][10]. Interleukin-6 (IL-6), a cytokine secreted by stimulated monocytes and macrophages, mediates a broad range of biological reactions [20][11]. Plasma IL-6 increases only 1 h after bodily insult and peaks after about 3–6 h [21,22][12][13]. Measurably increased IL-6 levels have been noted following trauma, stress, and infection [20][11]. A multifunctional cytokine that transmits cell signals and regulates immune cells, IL-6 has a strong proinflammatory effect associated with multiple biological functions and plays an important role in inflammation, tumor growth, and hematological diseases [23,24][14][15]. IL-6 triggers multiple immune responses by forming a positive feedback loop that eventually results in a cytokine storm, and elevated serum IL-6 may indicate disease severity and prognosis. Among COVID-19 patients admitted to the hospital, IL-6 was higher in the non-survival group than in the survival group [25,26][16][17]. Many studies have recognized IL-6 as a pivotal marker for implying the prognosis and severity of various diseases [27,28,29,30][18][19][20][21]. In addition, serum IL-6 may be useful for monitoring treatment response and evaluating the efficacy of medications such as tocilizumab, an IL-6 receptor blockade used for treating severe COVID-19 infections [19,31][10][22].

1.2. C-Reactive Protein, Procalcitonin and Ferritin

As serum cytokines such as IL-6 and TNF-α are released, they further stimulate several downstream immune pathways, increasing the production of acute-phase reactants such as C-reactive protein (CRP) and procalcitonin (PCT). CRP is a non-specific acute-phase protein induced by IL-6 in the liver and a sensitive biomarker of inflammation, infection, and tissue damage [38][23].
CRP level is usually low in the bloodstream. Following acute inflammatory reactions, serum CRP increases significantly within 12–24 h, with a 20–72 h plateau and a subsequent return to baseline levels in 3–7 days [39,40,41][24][25][26]. As most CRP components are synthesized in the liver, liver failure would hinder the production of CRP [42][27]. COVID-19 patients with higher serum CRP are prone to evolve to severe disease states [43][28]. Among these COVID-19 patients, higher circulating CRP is associated with a higher rate of adverse events, such as venous thromboembolism events, acute kidney injury, and higher in-hospital mortality [44][29].
Procalcitonin (PCT), the precursor of calcitonin, is a glycoprotein consisting of a 116-amino acid, which is typically synthesized and released by thyroid parafollicular C cell [45,46][30][31]. Procalcitonin increases within four hours of response to infection or acute injury as an acute inflammatory marker, peaks at 6 h with a plateau at 8–24 h, and a return to baseline levels in 2–3 days [41][26]. Increased serum PCT level is associated with a high risk of bacterial infections and sepsis rather than viral infections, and PCT has previously been used to distinguish between bacterial and viral infections [47][32]. However, elevated PCT levels are correlated with the severity of SARS-CoV-2 infection [48,49,50][33][34][35]. Compared to moderate COVID-19 patients with abnormal image findings and clinical symptoms only, severe cases demonstrated a four to eight times higher procalcitonin level during severe or critical SARS-CoV-2 infection, respectively [50][35]. PCT levels appear to be useful as a disease severity predictor and may further imply concomitant bacterial infections. Co-infection rates were higher during severe SARS-CoV-2 infection and were accompanied by raised PCT levels [50][35]. For this reason, gradually increasing serum PCT levels may indicate a poorer prognosis.
Ferritin, an acute-phase protein, may interfere with iron metabolism [51][36]. Iron parameters, such as ferritin and transferrin, are not yet considered standard biomarkers for monitoring COVID-19 disease progression because the relationship between iron metabolism and COVID-19 remains unclear [52][37]. Some studies have claimed that elevated ferritin is a risk factor for COVID-19 severity [53,54,55][38][39][40].

2. Hematological Abnormality

SARS-CoV-2 infection alters the hematopoietic system and hemostasis, causing hematological abnormality and coagulopathy.
Lymphocytopenia, a hallmark of COVID-19, may be considered a crucial laboratory finding in terms of being a prognostic predictor. The degree of lymphopenia is correlated with the severity of the disease, while absolute lymphocyte counts (ALC) lower than 1000/mm3 indicate a poor prognosis [56][41]. The pathological mechanism of lymphopenia during severe COVID-19 disease states remains unclear, but the current evidence has led to multiple hypothesized mechanisms: (1) because SARS-CoV-2 is known to affect tissues (lung, heart, gastrointestinal tract) and induce ACE2 expression in the process, and because lymphocytes express ACE2 receptor on their surface [57][42], SARS-CoV-2 may directly infect lymphocytes and induce lysis or apoptosis; (2) the cytokine storm, a significantly increased cytokine response provoked by SARS-CoV-2 infection, attributes significant elevation of interleukins (primarily IL-6, IL-2, IL-7, granulocyte colony-stimulating factor, interferon-γ inducible protein 10, MCP-1, and MIP1-a) and raised tumor necrosis factor (TNF)-α, which leads to lymphocyte apoptosis [58,59,60][43][44][45]; (3) coexisting lactic acidosis may interfere with lymphocyte proliferation [61][46]; and, (4) increased cytokines may also contribute to lymphoid organ atrophy (including the spleen) and further hinder lymphocyte turnover [62][47].
From an adaptive immunity perspective, SARS-CoV-2 infection influences total lymphocyte count and balance. This hematological presentation, the result of an increase in circulating pro-inflammatory cytokines, is most impactful in patients with severe COVID-19 infection, who have shown significant reductions in the absolute number of CD4+, CD8+, B, and natural killer (NK) cells [63,64][48][49]. Additionally, decreased numbers of other mononuclear leukocytes, such as monocytes, eosinophils, and basophils, have also been documented [65][50], and may provide a strong predictive value for in-hospital mortality, organ injury, and severe respiratory injury and complications [66][51].
Eosinopenia seems to have a significant role in COVID-19 diagnosis and prognosis, as significantly reduced eosinophils were found in severe cases [67,68][52][53]. Eosinophils are primarily responsible for allergic reactions and anti-parasitic infections [69][54]. Previous animal studies have demonstrated an antiviral effect of eosinophils in various respiratory infections [70,71][55][56]. Persistent eosinopenia was associated with higher mortality, but an increased eosinophil count was associated with disease improvement [72,73][57][58]. Interestingly, asthmatic patients with higher eosinophil counts have lower hospitalization rates and are less likely to succumb to severe disease. Patients with pre-existing conditions associated with eosinophilia, such as asthma or allergic rhinitis, may be more protected from severe SARS-CoV-2 infection [67][52].
Neutrophilia in COVID-19 patients may be also be used as a predictive marker for disease severity. Following SARS-CoV-2 infection, the increased emergence of immature neutrophils in the blood has been directly correlated with the severity of COVID-19 [74,75][59][60]. The recruitment of neutrophils from the circulation into tissues occurs in most organs, especially in highly vascularized areas such as the lungs and kidneys [76][61]. This influx of neutrophils somehow damages neighboring vessels and parenchyma. Neutrophils are provoked to release neutrophil extracellular traps (NETs) upon facing threat signals. NETs immobilize and limit pathogens and facilitate their killing by antimicrobial agents. However, excessive formation or impaired removal would endanger the host [77][62]. The dysregulated NET formation may contribute to direct vascular injury and indirectly induce autoimmune vasculitis by forming autoantibodies [78][63]. Histopathological evidence suggests that NET-induced immune-thrombosis is associated with thrombotic events and organ damage in severe COVID-19 infections [79][64].
Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have been recognized as essential independent predictive factors for identifying at-risk COVID-19 patients [80,81][65][66]. Elevated NLR or PLR indicate that patient health is deteriorating and that they require increased oxygen, and that they are at higher risk of developing acute respiratory distress syndrome (ARDS) [82][67]. The unique hematological manifestations of SARS-CoV-2 infections may indicate the possible utility of a prognostic test base on hematological responses. Continuous assessment of lymphocyte count dynamics may provide valuable information for predicting patient prognoses. At the point of symptom onset, patients presenting lower lymphocyte percentages have been associated with increased disease severity over time [83][68].

3. Organ Damage Indicator

3.1. Acute COVID–19 Cardiovascular Syndrome

A host of cardiovascular complications and involvements, called “acute COVID-19 cardiovascular syndrome”, occur during SARS-CoV-2 infection [91][69]. Acute coronary syndrome, myocardial injury, decompensated heart failure, stress-induced cardiomyopathy, pericardial effusion, viral myocarditis, or arrhythmia may be induced by various pathogenic routes following COVID-19 infection. Among patients with pre-existing cardiovascular comorbidities, cardiovascular diseases become more compromised or decompensated during COVID-19 infection. Systemic inflammatory response, thromboembolic events, and direct viral invasion compromise the cardiovascular system in COVID-19 patients, as do particular medication side-effects and hospital-acquired infections [91,92][69][70].

3.2. Cardiac Troponin

Myocardial injury is associated with poorer prognosis and outcome [91][69]. Cardiac troponins, consisting of troponin T, troponin I, and troponin C, are sensitive and specific for myocardial injury, and will appear elevated 4–10 h after acute myocardial ischemia [93][71]. They have been correlated with poor prognosis in cases involving pulmonary embolism or ischemic heart disease [92][70]. Cardiac complications have been more prevalent among COVID-19 cases compared to cases of SARS (severe acute respiratory syndrome). Epidemiological evidence indicates that 12% to 20% of hospitalized patients with COVID-19 have cardiac injuries, as implied by raised cardiac troponin levels [91,94][69][72]. For this reason, cardiac troponin may be useful as a potential prognostic marker to estimate patient outcome and mortality risk.

3.3. Brain Type NPs and N-Terminal Pro-BNP

Plasma natriuretic peptides (NPs), such as BNP (brain type NPs) and N-terminal pro-BNP (NT-proBNP), are commonly examined to evaluate acute heart failure (HF) patients [95][73]. Elevated NT-proBNP levels are associated with higher in-hospital mortality rates in COVID-19 cases [96][74] and provide more predictive value in combination with cardiac troponin [97][75]. However, although higher serum brain natriuretic peptide levels have been associated with cardiogenic pulmonary edema in COVID-19 patients with ARDS, some may have high levels of brain natriuretic peptide without significant ventricular dysfunction [98][76]. These cardiac biomarkers should be carefully considered when evaluating heart failure, as there are multiple mechanisms of cardiac injury. A point-of-care cardiac ultrasound should be considered to assess heart function to tailor treatment [98][76].

3.4. COVID 19-Associated Acute Renal Injury

In addition to the pulmonary manifestations associated with COVID-19, acute kidney injury (AKI) is a common complication during SARS-CoV-2 infection. Several pathogeneses injure renal tissues: local or systemic inflammatory responses and reactions, endothelial injury, coagulation-induced thromboembolic event, and renin–angiotensin system activation [99][77]. According to Kidney Disease Improving Global Outcomes (KDIGO), guidelines, which provides the consensus definition of AKI, previous studies have reported that nearly 30–50% of hospitalized patients with COVID-19 develop some form of AKI [100,101,102][78][79][80]. Near half of all patients in intensive care units (ICU) with acute kidney injury require renal replacement therapy [101[79][80],102], and in-hospital mortality is higher among patients with acute kidney injury [99][77]. The clinical manifestations of renal function deterioration range from mild proteinuria/hematuria to a drop in glomerular filtration rate (GFR), increased serum creatinine, or evolution to chronic kidney disease [99][77]. Notably, patients with pre-existing chronic kidney disease are vulnerable to severe clinical presentations and higher mortality [103][81]. For these reasons, deteriorated renal function or pre-existing renal disease during COVID-19 infection may indicate a poorer prognosis.

3.5. Markers for Other End-Organ Injury

Lactate dehydrogenase, an enzyme ubiquitously present in all human tissue, can be used as an indicator of gluconeogenesis and DNA metabolism [104][82]. Inflammatory responses and thromboembolic events hinder microcirculatory function and compromise oxygen delivery, increasing the likelihood of gluconeogenesis and DNA metabolism. Higher serum LDH might, therefore, be used to indicate COVID-19 disease severity and predict mortality risk [105,106,107][83][84][85].
Furthermore, higher serum lactate level is frequently considered an indicator of organ hypoperfusion or tissue hypoxia and is associated with more severe COVID-19 conditions. Higher serum lactate level is associated with poor prognosis and higher mortality [108,109][86][87].

3.6. Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is a rare but severe condition associated with post-COVID-19 infection in which various body parts become inflamed. MIS may involve the heart, lungs, kidneys, brain, skin, eyes, and/or the gastrointestinal organs. The presence of the symptoms in people <21 years old (or ≤19 years old per the World Health Organization definition is defined as MIS-children (MIS-C), and the presence of symptoms in people >21 years old is defined as MIS-adult (MIS-A). MIS-C is more common than MIS-A [8,110][88][89]. MIS shares similar clinical features with Kawasaki disease, an acute pediatric medium-vessel vasculitis. Symptoms, which include fever, elevated inflammatory markers, and multiple organ dysfunction, develop during or after SARS-CoV-2 infection [111][90].
Additional MIS-associated abnormalities include leukopenia/lymphopenia, elevated serum D-dimer, PCT, creatine kinase, and IL-6. Moreover, children with severe complications may have higher CRP, procalcitonin, or troponin levels and lower lymphocyte/platelet count [112,113][91][92]. The biomarkers listed in Table 21 may help establish the relationship between diagnostic criteria and clinical presentations [110,113][89][92].
Table 21. Diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C) [110,114].
Diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C) [89][93].
World Health OrganizationCenters for Disease Control and Prevention (United States) *
  • Children and adolescents 0–19 years of age with fever > 3 days
    AND
  • Two of the following:
    ◆
    Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet).
    ◆
    Hypotension or shock.
    ◆
    Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP),
    ◆
    Evidence of coagulopathy (by PT, PTT, elevated d-Dimers).
    ◆
    Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain).
    AND
  • Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin.
    AND
  • No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal, or streptococcal shock syndromes.
    AND
  • Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19.
  • An individual aged <21 years presenting with fever >38.0 °C for ≥24 h
  • Laboratory evidence of inflammation, > 1 finding
    ◆
    An elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes, and low albumin
  • Evidence of clinically severe illness requiring hospitalization, with >2 organ involvement
    ◆
    Cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurological);
    AND
  • No alternative plausible diagnoses.
    AND
  • Positive for current or recent SARS-CoV-2 infection
    ◆
    Confirmed by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.
* (1) Some individuals may fulfill full or partial criteria for Kawasaki disease but should be reported if they meet the case definition for MIS-C. (2) Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection.

References

  1. Badulak, J.; Antonini, M.V.; Stead, C.M.; Shekerdemian, L.; Raman, L.; Paden, M.L.; Agerstrand, C.; Bartlett, R.H.; Barrett, N.; Combes, A.; et al. Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization. ASAIO J. 2021, 67, 485–495.
  2. Bortolotti, D.; Gentili, V.; Rizzo, S.; Schiuma, G.; Beltrami, S.; Strazzabosco, G.; Fernandez, M.; Caccuri, F.; Caruso, A.; Rizzo, R. TLR3 and TLR7 RNA Sensor Activation during SARS-CoV-2 Infection. Microorganisms 2021, 9, 1820.
  3. Tabassum, T.; Rahman, A.; Araf, Y.; Ullah, A.; Hosen, M.J. Prospective selected biomarkers in COVID-19 diagnosis and treatment. Biomark. Med. 2021, 15, 1435–1449.
  4. Samprathi, M.; Jayashree, M. Biomarkers in COVID-19: An Up-To-Date Review. Front. Pediatr. 2021, 8, 607647.
  5. Yang, L.; Xie, X.; Tu, Z.; Fu, J.; Xu, D.; Zhou, Y. The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduct. Target. Ther. 2021, 6, 255.
  6. Catanzaro, M.; Fagiani, F.; Racchi, M.; Corsini, E.; Govoni, S.; Lanni, C. Immune response in COVID-19: Addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct. Target. Ther. 2020, 5, 84.
  7. Ragab, D.; Eldin, H.S.; Taeimah, M.; Khattab, R.; Salem, R. The COVID-19 Cytokine Storm; What We Know So Far. Front. Immunol. 2020, 11, 1446.
  8. Du, P.; Geng, J.; Wang, F.; Chen, X.B.; Huang, Z.W.; Wang, Y. Role of IL-6 inhibitor in treatment of COVID-19-related cytokine release syndrome. Int. J. Med. Sci. 2021, 18, 1356–1362.
  9. Mojtabavi, H.; Saghazadeh, A.; Rezaei, N. Interleukin-6 and severe COVID-19: A systematic review and meta-analysis. Eur. Cytokine Netw. 2020, 31, 44–49.
  10. Giannakodimos, I.; Gkountana, G.-V.; Lykouras, D.; Karkoulias, K.; Tsakas, S. The Role of Interleukin-6 in the Pathogenesis, Prognosis and Treatment of Severe COVID-19. Curr. Med. Chem. 2021, 28, 5328–5338.
  11. Zaric, B.; Andrijevic, I.; Matijasevic, J.; Andrijevic, L.; Kovacevic, T.; Zaric, B. Interleukin-6 and procalcitonin as biomarkers in mortality prediction of hospitalized patients with community acquired pneumonia. Ann. Thorac. Med. 2014, 9, 162–167.
  12. Shimazui, T.; Matsumura, Y.; Nakada, T.; Oda, S. Serum levels of interleukin-6 may predict organ dysfunction earlier than SOFA score. Acute Med. Surg. 2017, 4, 255–261.
  13. Gebhard, F.; Pfetsch, H.; Steinbach, G.; Strecker, W.; Kinzl, L.; Brückner, U.B. Is interleukin 6 an early marker of injury severity following major trauma in humans? Arch. Surg. 2000, 135, 291–295.
  14. Lai, H.-S.; Lin, W.-H.; Lai, S.-L.; Lin, H.-Y.; Hsu, W.-M.; Chou, C.-H.; Lee, P.-H. Interleukin-6 Mediates Angiotensinogen Gene Expression during Liver Regeneration. PLoS ONE 2013, 8, e67868.
  15. Taniguchi, K.; Karin, M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. In Seminars in Immunology; Elsevier: Amsterdam, The Netherlands, 2014.
  16. Chen, R.; Sang, L.; Jiang, M.; Yang, Z.; Jia, N.; Fu, W.; Xie, J.; Guan, W.; Liang, W.; Ni, Z.; et al. Longitudinal hematologic and immunologic variations associated with the progression of COVID-19 patients in China. J. Allergy Clin. Immunol. 2020, 146, 89–100.
  17. Liu, T.; Zhang, J.; Yang, Y.; Ma, H.; Li, Z.; Zhang, J.; Cheng, J.; Zhang, X.; Zhao, Y.; Xia, Z.; et al. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol. Med. 2020, 12, e12421.
  18. Song, J.; Park, D.W.; Moon, S.; Cho, H.-J.; Park, J.H.; Seok, H.; Choi, W.S. Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: A prospective controlled study according to the Sepsis-3 definitions. BMC Infect. Dis. 2019, 19, 968.
  19. Weidhase, L.; Wellhöfer, D.; Schulze, G.; Kaiser, T.; Drogies, T.; Wurst, U.; Petros, S. Is Interleukin-6 a better predictor of successful antibiotic therapy than procalcitonin and C-reactive protein? A single center study in critically ill adults. BMC Infect. Dis. 2019, 19, 150.
  20. Emami, A.M.; Zaerin, O. Role of Serum Interleukin 6, Albumin and C-Reactive Protein in COPD Patients. Tanaffos 2015, 14, 134–140.
  21. Jekarl, D.W.; Lee, S.-Y.; Lee, J.; Park, Y.-J.; Kim, Y.; Park, J.H.; Wee, J.H.; Choi, S.P. Procalcitonin as a diagnostic marker and IL-6 as a prognostic marker for sepsis. Diagn. Microbiol. Infect. Dis. 2013, 75, 342–347.
  22. Galván-Román, J.M.; Rodríguez-García, S.C.; Roy-Vallejo, E.; Marcos-Jiménez, A.; Sánchez-Alonso, S.; Fernández-Díaz, C.; Alcaraz-Serna, A.; Mateu-Albero, T.; Rodríguez-Cortes, P.; Sánchez-Cerrillo, I.; et al. IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study. J. Allergy Clin. Immunol. 2020, 147, 72–80.
  23. Pepys, M.B.; Hirschfield, G. C-reactive protein: A critical update. J. Clin. Investig. 2003, 111, 1805–1812.
  24. Hahn, W.-H.; Song, J.-H.; Kim, H.; Park, S. Is procalcitonin to C-reactive protein ratio useful for the detection of late onset neonatal sepsis? J. Matern.-Fetal Neonatal Med. 2018, 31, 822–826.
  25. Mooiweer, E.; Luijk, B.; Bonten, M.J.; Ekkelenkamp, M.B. C-reactive protein levels but not CRP dynamics predict mortality in patients with pneumococcal pneumonia. J. Infect. 2011, 62, 314–316.
  26. Rowland, T.; Hilliard, H.; Barlow, G. Chapter Three-Procalcitonin: Potential Role in Diagnosis and Management of Sepsis. In Advances in Clinical Chemistry; Makowski, G.S., Ed.; Elsevier: Amsterdam, The Netherlands, 2015; pp. 71–86.
  27. Sproston, N.R.; Ashworth, J.J. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front. Immunol. 2018, 9, 754.
  28. Liu, F.; Li, L.; Xu, M.; Wu, J.; Luo, D.; Zhu, Y.; Li, B.; Song, X.; Zhou, X. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J. Clin. Virol. 2020, 127, 104370.
  29. Smilowitz, N.R.; Kunichoff, D.; Garshick, M.; Shah, B.; Pillinger, M.; Hochman, J.S.; Berger, J.S. C-reactive protein and clinical outcomes in patients with COVID-19. Eur. Heart J. 2021, 42, 2270–2279.
  30. Choi, J.J.; McCarthy, M.W. Novel applications for serum procalcitonin testing in clinical practice. Expert Rev. Mol. Diagn. 2017, 18, 27–34.
  31. Saeed, K.; Dale, A.P.; Leung, E.; Cusack, T.; Mohamed, F.; Lockyer, G.; Arnaudov, S.; Wade, A.; Moran, B.; Lewis, G.; et al. Procalcitonin levels predict infectious complications and response to treatment in patients undergoing cytoreductive surgery for peritoneal malignancy. Eur. J. Surg. Oncol. 2015, 42, 234–243.
  32. Rodríguez, A.; Reyes, L.; Monclou, J.; Suberviola, B.; Bodí, M.; Sirgo, G.; Solé-Violán, J.; Guardiola, J.; Barahona, D.; Díaz, E.; et al. Relationship between acute kidney injury and serum procalcitonin (PCT) concentration in critically ill patients with influenza infection. Med. Intensiv. 2018, 42, 399–408.
  33. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus—Infected Pneumonia in Wuhan, China. JAMA 2020, 323, 1061–1069.
  34. Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Ou, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.; Hui, D.S.C.; et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020, 382, 1708–1720.
  35. Hu, R.; Han, C.; Pei, S.; Yin, M.; Chen, X. Procalcitonin levels in COVID-19 patients. Int. J. Antimicrob. Agents 2020, 56, 106051.
  36. Narazaki, M.; Kishimoto, T. The Two-Faced Cytokine IL-6 in Host Defense and Diseases. Int. J. Mol. Sci. 2018, 19, 3528.
  37. Banchini, F.; Cattaneo, G.M.; Capelli, P. Serum ferritin levels in inflammation: A retrospective comparative analysis between COVID-19 and emergency surgical non-COVID-19 patients. World J. Emerg. Surg. 2021, 16, 9.
  38. Lin, Z.; Long, F.; Yang, Y.; Chen, X.; Xu, L.; Yang, M. Serum ferritin as an independent risk factor for severity in COVID-19 patients. J. Infect. 2020, 81, 647–679.
  39. Kappert, K.; Jahić, A.; Tauber, R. Assessment of serum ferritin as a biomarker in COVID-19: Bystander or participant? Insights by comparison with other infectious and non-infectious diseases. Biomarkers 2020, 25, 616–625.
  40. Huang, I.; Pranata, R.; Lim, M.A.; Oehadian, A.; Alisjahbana, B. C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: A meta-analysis. Ther. Adv. Respir. Dis. 2020, 14, 1753466620937175.
  41. Lee, J.; Park, S.-S.; Kim, T.; Lee, D.-G.; Kim, D.-W. Lymphopenia as a Biological Predictor of Outcomes in COVID-19 Patients: A Nationwide Cohort Study. Cancers 2021, 13, 471.
  42. Xu, H.; Zhong, L.; Deng, J.; Peng, J.; Dan, H.; Zeng, X.; Li, T.; Chen, Q. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int. J. Oral Sci. 2020, 12, 8.
  43. Aggarwal, S.; Gollapudi, S.; Gupta, S. Increased TNF-α-induced apoptosis in lymphocytes from aged humans: Changes in TNF-α receptor expression and activation of caspases. J. Immunol. 1999, 162, 2154–2161.
  44. Liao, Y.-C.; Liang, W.-G.; Chen, F.-W.; Hsu, J.-H.; Yang, J.-J.; Chang, M.-S. IL-19 Induces Production of IL-6 and TNF-α and Results in Cell Apoptosis Through TNF-α. J. Immunol. 2002, 169, 4288–4297.
  45. Singh, S.; Sharma, A.; Arora, S.K. High producer haplotype (CAG) of-863C/A,-308G/A and-238G/A poly-morphisms in the promoter region of TNF-α gene associate with enhanced apoptosis of lymphocytes in HIV-1 subtype C infected individuals from North India. PLoS ONE 2014, 9, e98020.
  46. You, B.; Ravaud, A.; Canivet, A. The official French guidelines to protect patients with cancer against SARS-CoV-2 infection. Lancet Oncol. 2020, 21, 619–621.
  47. Fischer, K.; Hoffmann, P.; Voelkl, S.; Meidenbauer, N.; Ammer, J.; Edinger, M.; Gottfried, E.; Schwarz, S.; Rothe, G.; Hoves, S.; et al. Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood 2007, 109, 3812–3819.
  48. Xu, Z.; Shi, L.; Wang, Y.; Zhang, J.; Huang, L.; Zhang, C.; Shuhong, L.; Peng, Z.; Hongxia, L.; Li, Z.; et al. Pathological findings of COVID-19 associated with acute respiratory dis-tress syndrome. Lancet Respir. Med. 2020, 8, 420–422.
  49. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506.
  50. Qin, C.; Zhou, L.; Hu, Z.; Zhang, S.; Yang, S.; Tao, Y.; Xie, C.; Ma, K.; Shang, K.; Wang, W.; et al. Dysregulation of Immune Response in Patients with Coronavirus 2019 (COVID-19) in Wuhan, China. Clin. Infect. Dis. 2020, 71, 762–768.
  51. Li, D.; Chen, Y.; Liu, H.; Jia, Y.; Li, F.; Wang, W.; Wu, J.; Wan, Z.; Cao, Y.; Zeng, R. Immune dysfunction leads to mortality and organ injury in patients with COVID-19 in China: Insights from ERS-COVID-19 study. Signal Transduct. Target. Ther. 2020, 5, 1–3.
  52. Dastoli, S.; Bennardo, L.; Patruno, C.; Nisticò, S.P. Are erythema multiforme and urticaria related to a better outcome of COVID -19? Dermatol. Ther. 2020, 33, e13681.
  53. Dosanjh, A. Eosinophil-Derived Neurotoxin and Respiratory Tract Infection and Inflammation: Implications for COVID-19 Management. J. Interf. Cytokine Res. 2020, 40, 443–445.
  54. Rosenberg, H.F.; Foster, P.S. Eosinophils and COVID-19: Diagnosis, prognosis, and vaccination strategies. Semin. Immunopathol. 2021, 43, 383–392.
  55. Adamko, D.J.; Yost, B.L.; Gleich, G.J.; Fryer, A.; Jacoby, D. Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection: Eosinophils mediate airway hyperresponsiveness, M2 muscarinic receptor dysfunction, and antiviral effects. J. Exp. Med. 1999, 190, 1465–1478.
  56. Samarasinghe, A.E.; Melo, R.C.N.; Duan, S.; LeMessurier, K.; Liedmann, S.; Surman, S.L.; Lee, J.J.; Hurwitz, J.L.; Thomas, P.G.; McCullers, J.A. Eosinophils Promote Antiviral Immunity in Mice Infected with Influenza A Virus. J. Immunol. 2017, 198, 3214–3226.
  57. Du, Y.; Tu, L.; Zhu, P.; Mu, M.; Wang, R.; Yang, P.; Wang, X.; Hu, C.; Ping, R.; Hu, P.; et al. Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan. A Retrospective Observational Study. Am. J. Respir. Crit. Care Med. 2020, 201, 1372–1379.
  58. Zhang, J.J.; Dong, X.; Cao, Y.Y.; Yuan, Y.D.; Yang, Y.B.; Yan, Y.Q.; Akdis, C.A.; Gao, Y.D. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy 2020, 75, 1730–1741.
  59. Schulte-Schrepping, J.; Reusch, N.; Paclik, D.; Baßler, K.; Schlickeiser, S.; Zhang, B.; Krämer, B.; Krammer, T.; Brumhard, S.; Bonaguro, L.; et al. Severe COVID-19 is marked by a dysregulated mye-loid cell compartment. Cell 2020, 182, 1419–1440.
  60. Wilk, A.J.; Rustagi, A.; Zhao, N.Q.; Roque, J.; Martínez-Colón, G.J.; McKechnie, J.L.; Ivison, G.T.; Ranganath, T.; Vergara, R.; Hollis, T.; et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat. Med. 2020, 26, 1070–1076.
  61. Liu, Y.; Du, X.; Chen, J.; Jin, Y.; Peng, L.; Wang, H.H.; Luo, M.; Chen, L.; Zhao, Y. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J. Infect. 2020, 81, e6–e12.
  62. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 2017, 18, 134–147.
  63. Hakkim, A.; Fürnrohr, B.G.; Amann, K.; Laube, B.; Abu Abed, U.; Brinkmann, V.; Herrmann, M.; Voll, R.E.; Zychlinsky, A. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl. Acad. Sci. USA 2010, 107, 9813–9818.
  64. Morris, G.; Bortolasci, C.C.; Puri, B.K.; Olive, L.; Marx, W.; O’Neil, A.; Athan, E.; Carvalho, A.; Maes, M.; Walder, K.; et al. Preventing the development of severe COVID-19 by modifying immunothrombosis. Life Sci. 2020, 264, 118617.
  65. Liu, Q.; Chen, H.; Zeng, Q. Clinical characteristics of COVID-19 patients with complication of cardiac arrhythmia. J. Infect. 2020, 81, e6–e8.
  66. Simadibrata, D.M.; Pandhita, B.A.W.; Ananta, M.E.; Tango, T. Platelet-to-lymphocyte ratio, a novel biomarker to predict the severity of COVID-19 patients: A systematic review and meta-analysis. J. Intensiv. Care Soc. 2020.
  67. Wu, C.; Chen, X.; Cai, Y.; Xia, J.; Zhou, X.; Xu, S.; Huang, H.; Zhang, L.; Zhou, X.; Du, C.; et al. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern. Med. 2020, 180, 934–943.
  68. Tan, L.; Wang, Q.; Zhang, D.; Ding, J.; Huang, Q.; Tang, Y.-Q.; Wang, Q.; Miao, H. Lymphopenia predicts disease severity of COVID-19: A descriptive and predictive study. Signal Transduct. Target. Ther. 2020, 5, 1–3.
  69. Hendren, N.S.; Drazner, M.H.; Bozkurt, B.; Cooper, L.T., Jr. Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome. Circulation 2020, 141, 1903–1914.
  70. Khan, S.; Rasool, S.T.; Ahmed, S.I. Role of Cardiac Biomarkers in COVID-19: What Recent Investigations Tell Us? Curr. Probl. Cardiol. 2021, 46, 100842.
  71. Garg, P.; Morris, P.; Fazlanie, A.L.; Vijayan, S.; Dancso, B.; Dastidar, A.G.; Plein, S.; Mueller, C.; Haaf, P. Cardiac biomarkers of acute coronary syndrome: From history to high-sensitivity cardiac troponin. Intern. Emerg. Med. 2017, 12, 147–155.
  72. Bozkurt, B.; Kamat, I.; Hotez, P.J. Myocarditis With COVID-19 mRNA Vaccines. Circulation 2021, 144, 471–484.
  73. Selçuk, M.; Keskin, M.; Çınar, T.; Günay, N.; Doğan, S.; Çiçek, V.; Kılıç, Ş.; Asal, S.; Yavuz, S.; Keser, N.; et al. Prognostic significance of N-Terminal Pro-BNP in patients with COVID-19 pneumonia without previous history of heart failure. J. Cardiovasc. Thorac. Res. 2021, 13, 141–145.
  74. Gao, L.; Jiang, D.; Wen, X.-S.; Cheng, X.-C.; Sun, M.; He, B.; You, L.-N.; Lei, P.; Tan, X.-W.; Qin, S.; et al. Prognostic value of NT-proBNP in patients with severe COVID-19. Respir. Res. 2020, 21, 83.
  75. Calvo-Fernández, A.; Izquierdo, A.; Subirana, I.; Farré, N.; Vila, J.; Durán, X.; García-Guimaraes, M.; Valdivielso, S.; Cabero, P.; Soler, C.; et al. Marcadores de daño miocárdico en la predicción del pronóstico a corto plazo de los pacientes con COVID-19. Rev. Española Cardiol. 2020, 74, 576–583.
  76. Ranard, L.S.; Fried, J.A.; Abdalla, M.; Anstey, D.; Givens, R.C.; Kumaraiah, D.; Kodali, S.K.; Takeda, K.; Karmpaliotis, D.; Rabbani, L.E.; et al. Approach to Acute Cardiovascular Complications in COVID-19 Infection. Circ. Heart Fail. 2020, 13, e007220.
  77. Legrand, M.; Bell, S.; Forni, L.; Joannidis, M.; Koyner, J.L.; Liu, K.; Cantaluppi, V. Pathophysiology of COVID-19-associated acute kidney injury. Nat. Rev. Nephrol. 2021, 17, 751–764.
  78. Cheng, Y.; Luo, R.; Wang, K.; Zhang, M.; Wang, Z.; Dong, L.; Li, J.; Yao, Y.; Ge, S.; Xu, G. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020, 97, 829–838.
  79. Mohamed, M.M.; Lukitsch, I.; Torres-Ortiz, A.E.; Walker, J.B.; Varghese, V.; Hernandez-Arroyo, C.F.; Alqudsi, M.; LeDoux, J.R.; Velez, J.C.Q. Acute Kidney Injury Associated with Coronavirus Disease 2019 in Urban New Orleans. Kidney360 2020, 1, 614–622.
  80. Cummings, M.J.; Baldwin, M.R.; Abrams, D.; Jacobson, S.D.; Meyer, B.J.; Balough, E.M.; Aaron, J.G.; Claassen, J.; LeRoy, E.R.; Hastie, J. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: A prospective cohort study. Lancet 2020, 395, 1763–1770.
  81. Zarębska-Michaluk, D.; Jaroszewicz, J.; Rogalska, M.; Lorenc, B.; Rorat, M.; Szymanek-Pasternak, A.; Piekarska, A.; Berkan-Kawińska, A.; Sikorska, K.; Tudrujek-Zdunek, M.; et al. Impact of Kidney Failure on the Severity of COVID-19. J. Clin. Med. 2021, 10, 2042.
  82. Farhana, A.; Lappin, S.L. Biochemistry, Lactate Dehydrogenase; StatPearls Publishing: Treasure Island, FL, USA, 2022. Available online: https://www.ncbi.nlm.nih.gov/books/NBK557536/ (accessed on 7 May 2021).
  83. Vidal-Cevallos, P.; Higuera-De-La-Tijera, F.; Chávez-Tapia, N.C.; Sanchez-Giron, F.; Cerda-Reyes, E.; Rosales-Salyano, V.H.; Servin-Caamaño, A.; Vázquez-Medina, M.U.; Méndez-Sánchez, N. Lactate-dehydrogenase associated with mortality in hospitalized patients with COVID-19 in Mexico: A multi-centre retrospective cohort study. Ann. Hepatol. 2021, 24, 100338.
  84. Szarpak, L.; Ruetzler, K.; Safiejko, K.; Hampel, M.; Pruc, M.; Koda, L.K.; Filipiak, K.J.; Jaguszewski, M.J. Lactate dehydrogenase level as a COVID-19 severity marker. Am. J. Emerg. Med. 2020, 45, 638–639.
  85. Martha, J.W.; Wibowo, A.; Pranata, R. Prognostic value of elevated lactate dehydrogenase in patients with COVID-19: A systematic review and meta-analysis. Postgrad. Med. J. 2021.
  86. Carpenè, G.; Onorato, D.; Nocini, R.; Fortunato, G.; Rizk, J.G.; Henry, B.M.; Lippi, G. Blood lactate concentration in COVID-19: A systematic literature review. Clin. Chem. Lab. Med. (CCLM) 2021, 60, 332–337.
  87. Bruno, R.R.; Wernly, B.; Flaatten, H.; Fjølner, J.; Artigas, A.; Pinto, B.B.; Schefold, J.C.; Binnebössel, S.; Baldia, P.H.; Kelm, M.; et al. Lactate is associated with mortality in very old intensive care patients suffering from COVID-19: Results from an international observational study of 2860 patients. Ann. Intensive Care 2021, 11, 128.
  88. Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome (MIS). Updated 25 June 2021. Available online: https://www.cdc.gov/mis/about.html (accessed on 11 January 2022).
  89. WHO. Multisystem Inflammatory Syndrome in Children and Adolescents Temporally Related to COVID-19. Updated 15 May 2020. Available online: https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19 (accessed on 22 January 2022).
  90. Nalbandian, A.; Sehgal, K.; Gupta, A.; Madhavan, M.V.; McGroder, C.; Stevens, J.S.; Cook, J.R.; Nordvig, A.S.; Shalev, D.; Sehrawat, T.S.; et al. Post-acute COVID-19 syndrome. Nat. Med. 2021, 27, 601–615.
  91. Pierce, C.A.; Preston-Hurlburt, P.; Dai, Y.; Aschner, C.B.; Cheshenko, N.; Galen, B.; Garforth, S.J.; Herrera, N.G.; Jangra, R.K.; Morano, N.C.; et al. Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients. Sci. Transl. Med. 2020, 12.
  92. Fernandes, D.M.; Oliveira, C.R.; Guerguis, S.; Eisenberg, R.; Choi, J.; Kim, M.; Abdelhemid, A.; Agha, R.; Agarwal, S.; Aschner, J.L.; et al. Severe Acute Respiratory Syndrome Coronavirus 2 Clinical Syndromes and Predictors of Disease Severity in Hospitalized Children and Youth. J. Pediatr. 2021, 230, 23–31.
  93. Centers for Disease Control and Prevention. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C). Updated 20 May 2021. Available online: https://www.cdc.gov/mis/mis-c/hcp/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fmis%2Fhcp%2Findex.html (accessed on 22 January 2022).
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback